PySB implementations of Bcl2-models from the group of Pingping Shen, along with
other derived, closely related models.

In a series of papers from 2007-2010, the research group of Pingping Shen
implemented and investigated models of Bcl-2 family interactions. In this file
we have re-implemented these models using PySB. We have also included a model
from [Howells2011] which is a fairly straightforward extension of a
Shen group model from [Chen2007biophysj].

In the original papers, species quantities and forward rate constants were
either given in units of micromolar ([Chen2007biophysj], [Howells2011]) or
nanomolar ([Chen2007febs], [Cui2008]). For consistency, these values have
been written in terms of their molar equivalents (for example, 0.1uM = 0.1e-6 M;
3 uM^-1 s^1 = 3e6 M^-1 s^-1). Concentrations have been converted into units of
numbers of molecules according to:

No. of molecules = Conc * N_A * vol

where N_A is Avogadro’s number and vol is the cell volume, which is given a
default value in the global variable V defined in shared.py.
Similarly, forward rate constants are converted into stochastic rate constants
according to:

Declares the signatures of the Bcl-2 family monomers used in all of the
Shen models.

In principle, each Shen MOMP model implementation could declare its own
set of Bcl-2 monomers, each with its own site and state signature. In the
interest of consistency, a unified set of monomer signatures that supports
all of the models is defined here.

Uses the same model as the original EARM 1.0 ([Albeck2008]), in
which pore transport is modeled as binding of the cargo
(cytochrome C or Smac) to the active pore, and then release, in a
catalysis-like mechanism.

The initial conditions for cytochrome C and Smac, and the rate constants
for transport, are also taken from EARM 1.0.

Activation of Bax by an activator (tBid) in a one-step, hit-and-run
manner; Bax activation is reversible.

Bcl2 binds both tBid and Bax Bax can displace tBid from Bcl-2 (but not
the reverse).

If Bax oligomerization is incorporated into the model (see
do_pore_assembly argument, below), then this occurs as a spontaneous,
order 4 reaction.

This model combines both “direct” type and “indirect” type elements in
that Bcl-2 is capable of binding both Bid and Bax (see bind_table call
in the source code).

Parameters:

do_pore_assembly : True (default) or False

If True, adds the formation of Bax oligomers to the model. If False,
the model’s most downstream element is Bax activation. This is included
for two reasons: first, the original publication included two variant
models, one with and one without Bax oligomerization, so this allows
this aspect of the original models to be explored. Second, it allows
a model that extends this model to implement a different model of Bax
pore assembly (for example, as is the case with cui_direct).

do_pore_transport : True or False (default)

If True, adds the release of Cytochrome C and Smac to the model by
calling the function shen_pore_transport(). If CytoC/Smac
release are not incorporated into the model, the model matches the
originally published model but can’t be composed into the full
extrinsic apoptosis pathway.

This model builds on the model from [Chen2007biophysj],
implemented in chen_biophys_j(). The core reactions from the Chen
et al. model are the same, but Howells et al. modify some parameter values
and add a number of Bad-related reactions, including (see source code):